Novel benzimidazolone peptidomimetics as thrombin receptor antagonists

ABSTRACT

The invention is directed to novel benzimidazolone peptidomimetic compounds which are useful as thrombin receptor antagonists for the treatment of diseases associated with thrombosis, restenosis, hypertension, heart failure, arrhythmia, inflammation, angina, stroke, atherosclerosis, ischemic conditions, Angiogenesis related disorders, cancer, and neurodegenerative disorders. Pharmaceutical compositions comprising the substituted benzimidazolone peptidomimetics of the present invention and methods of treating conditions mediated by the thrombin receptor are also disclosed.

[0001] This patent application claims priority from provisional patentapplication Serial No. 60/141,552, which was filed Jun. 29, 1999. Thisinvention relates to certain novel thrombin receptor antagonists, theirsynthesis and their use for the treatment of diseases associated withthrombosis, restenosis, hypertension, heart failure, arrhythmia,inflammation, angina, stroke, atherosclerosis, ischemic conditions,Angiogenesis related disorders, cancer, and neurodegenerative disorders.

FIELD OF THE INVENTION BACKGROUND OF THE INVENTION

[0002] Thrombin is an important serine protease in hemostasis andthrombosis. One of the key actions of thrombin is cellular modulationvia receptor activation. A functional human thrombin receptor (PAR-1),cloned by Coughlin in 1991 (T.-K. Vu, Cell 1991, 64, 1057), was found tobe a member of the G-protein coupled receptor (GPCR) superfamily. Thereceptor activation putatively occurs by N-terminal recognition andproteolytic cleavage at the Arg-41/Ser-42 peptide bond to reveal atruncated N-terminus. This new receptor sequence, which has an SFLLRN(Ser-Phe-Leu-Leu-Arg-Asn) N-terminus acting as a tethered ligand torecognize a site on the receptor, can trigger activation and signaltransduction leading to platelet aggregation. Since 1991, three otherprotease-activated receptors with extensive homology to the thrombinreceptor, “PAR-2” (S. Nystedt, Proc. Natl. Acad. Sci USA 1994, 91,9208), “PAR-3” (H. Ishihara, Nature 1997, 386, 502), and “PAR-4” (W.-F.Xu, Proc. Natl. Acad. Sci USA 1998, 95, 6642), have been cloned.Thrombin receptor (PAR-1) specific antibody-induced blockade of theplatelet thrombin receptor has shown efficacy against arterialthrombosis in vivo (J. J. Cook Circulation 1995, 91, 2961). Hence,antagonists of the thrombin receptor (PAR-1) are useful to block theseprotease-activated receptors and, as such, may be used to treat plateletmediated thrombotic disorders such as myocardial infarction, stroke,restenosis, angina, atherosclerosis, and ischemic conditions.

[0003] The thrombin receptor (PAR-1) has also been identified on othercell types: endothelial, fibroblast, renal, osteosarcoma, smooth muscle,myocytes, tumor, and neuronal/glia. Thrombin activation of endothelialcells upregulates P-selectin to induce polymorphonuclear leukocyteadhesion—an inflammatory response of the vessel wall (Y. Sugama, J. CellBiol. 1992, 119, 935). In fibroblasts, thrombin receptor (PAR-1)activation induces proliferation and transmission of mitogenic signals(D. T. Hung, J. Cell Biol. 1992, 116, 827). Thrombin has been implicatedin osteoblast proliferation through its activation of osteoblast cells(D. N. Tatakis, Biochem. Biophys. Res. Commun. 1991, 174, 181). Thrombinhas been implicated in the regulation and retraction of neurons (K.Jalink, J. Cell. Biol. 1992, 118, 411). Therefore, in this context, theantagonist compounds of this invention may also be useful againstinflammation, osteoporosis, Angiogenesis related disorders, cancer,neurodegenerative disorders, hypertension, heart failure, arrhythmia,glomerulonephritis.

[0004] The compounds of the present invention are a structurally novelclass of benzimidazolone peptidomimetics represented by the generalformula (I) below.

SUMMARY OF THE INVENTION

[0005] The present invention is directed to structurally novel compoundsrepresented by the following general formula (I):

[0006] wherein

[0007] A₁ and A₂ are each independently a D- or L-amino acid selectedfrom the group consisting of alanine, β-alanine, arginine, homoarginine,cyclohexylalanine, citrulline, cysteine (optionally substituted withC₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), 2,4-diaminobutyric acid(optionally substituted with acyl, C₁-C₄ alkyl, aroyl, amidino, orMeC(NH)—), 2,3 diaminopropionic acid (optionally substituted with acyl,C₁-C₄ alkyl, aroyl, amidino, or MeC(NH)—), glutamine, glycine,indanylglycine, lysine (optionally substituted with acyl, C₁-C₄ alkyl,aroyl, MeC(NH)—), valine, methionine, proline, serine (optionallysubstituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), homoserine(optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl),tetrahydroisoquinoline-3-COOH, threonine (optionally substituted withC₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), ornithine (optionally substitutedwith acyl, C₁-C₄ alkyl, aroyl, MeC(NH)—), and an unsubstituted orsubstituted aromatic amino acid selected from the group consisting ofphenylalanine, heteroarylalanine, naphthylalanine, homophenylalanine,histidine, tryptophan, tyrosine, arylglycine, heteroarylglycine,aryl-β-alanine, and heteroaryl-β-alanine wherein the substituents on thearomatic amino acid are independently selected from one or more ofhalogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, C₁-C₄ alkoxycarbonyl,amino, amidino, guanidino, fluorinated C₁-C₄ alkyl, fluorinated C₁-C₄alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylcarbonyl, cyano, aryl,heteroaryl, arC₁-C₄ alkyl, C₂-C₄ alkenyl, alkynyl, or nitro;

[0008] Preferably, A₁ and A₂ are each independently an L-amino acidselected from the group consisting of alanine, β-alanine, arginine,homoarginine, cyclohexylalanine, citrulline, cysteine (optionallysubstituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl),2,4-diaminobutyric acid (optionally substituted with acyl, C₁-C₄ alkyl,aroyl, amidino, or MeC(NH)—), 2,3 diaminopropionic acid (optionallysubstituted with acyl, C₁-C₄ alkyl, aroyl, amidino, or MeC(NH)—),glutamine, glycine, indanylglycine, lysine (optionally substituted withacyl, C₁-C₄ alkyl, aroyl, MeC(NH)—), valine, methionine, proline, serine(optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl),homoserine (optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄alkyl), tetrahydroisoquinoline-3-COOH, threonine (optionally substitutedwith C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), ornithine (optionallysubstituted with acyl, C₁-C₄ alkyl, aroyl, MeC(NH)—), and anunsubstituted or substituted aromatic amino acid selected from the groupconsisting of phenylalanine, heteroarylalanine, naphthylalanine,homophenylalanine, histidine, tryptophan, tyrosine, arylglycine,heteroarylglycine, aryl-β-alanine, and heteroaryl-β-alanine wherein thesubstituents on the aromatic amino acid are independently selected fromone or more of halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, C₁-C₄alkoxycarbonyl, amino, amidino, guanidino, fluorinated C₁-C₄ alkyl,fluorinated C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylcarbonyl,cyano, aryl, heteroaryl, arC₁-C₄ alkyl, C₂-C₄ alkenyl, alkynyl, ornitro;

[0009] R₁ is selected from amino, C₁-C₈ alkylamino, C₁-C₈ dialkylamino,arylamino, arC₁-C₈ alkylamino, C₃-C₈ cycloalkylamino, heteroalkylC₁-C₈alkylamino, heteroalkylC₁-C₈ alkyl-N-methylamino, C₁-C₈dialkylaminoC₁-C₈ alkylamino, —N(C₁-C₈alkyl)-C₁-C₈ alkyl-N(C₁-C₈alkyl)₂,N(C₁-C₈ alkyl)(C₁-C₈ alkenyl), —N(C₁-C₈alkyl)(C₃-C₈cycloalkyl),heteroalkyl or substituted heteroalkyl wherein the substituent on theheteroalkyl is selected from oxo, amino, C₁-C₈ alkoxyC₁-C₈ alkyl, C₁-C₈alkylamino or C₁-C₈ dialkylamino;

[0010] Preferably, R₁ is selected from amino, C₁-C₆ alkylamino, C₁-C₆dialkylamino, arylamino, arC₁-C₆ alkylamino, heteroalkylC₁-C₆alkylamino, —N(C₁-C₆alkyl)-C₁-C₆alkyl-N(C₁-C₆alkyl)₂, heteroalkyl orsubstituted heteroalkyl wherein the substituent on the heteroalkyl isselected from oxo, amino, C₁-C₆alkoxyC₁-C₆ alkyl, C₁-C₆ alkylamino orC₁-C₆ dialkylamino;

[0011] R₂ and R₃ are each independently selected from hydrogen, C₁-C₈alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₈ alkyl, aryl, heteroalkyl,substituted heteroalkyl (wherein the substituent on the heteroalkyl isone or more substituents independently selected from C₁-C₈alkoxycarbonyl, C₁-C₈ alkyl, or C₁-C₄ alkylcarbonyl), heteroalkylC₁-C₈alkyl, indanyl, acetamidinoC₁-C₈ alkyl, aminoC₁-C₈ alkyl, C₁-C₈alkylaminoC₁-C₈ alkyl, C₁-C₈ dialkylaminoC₁-C₈ alkyl, unsubstituted orsubstituted heteroarylC₁-C₈ alkyl or unsubstituted or substitutedarC₁-C₈ alkyl, wherein the substituent on the aralkyl or heteroarylalkylgroup is one or more substituents independently selected from halogen,nitro, amino, C₁-C₈ alkyl, C₁-C₈ alkoxy, hydroxy, cyano, C₁-C₄alkylcarbonyl, C₁-C₈ alkoxycarbonyl, hydroxyC₁-C₈ alkyl oraminosulfonyl; or

[0012] R₂ and R₃ together with the nitrogen to which they are attached,alternatively form an unsubstituted or substituted heteroalkyl groupselected from piperidinyl, piperazinyl, morpholinyl or pyrrolidinyl,wherein the substituent is one or more substituents independentlyselected from C₁-C₈ alkyl C₁-C₈ alkoxycarbonyl or C₁-C₄ alkylcarbonyl;

[0013] Preferably, R₂ is selected from hydrogen or C₁-C₆ alkyl;

[0014] R₃ is selected from C₁-C₈ alkyl, C₃-C₆ cycloalkyl, C₃-C₆cycloalkylC₁-C₆ alkyl, aryl, heteroarylC₁-C₆ alkyl, substitutedheteroarylC₁-C₆ alkyl wherein the substituent is C₁-C₄ alkyl,heteroalkyl, heteroalkylC₁-C₆ alkyl, indanyl, acetamidinoC₁-C₆ alkyl,aminoC₁-C₆ alkyl, C₁-C₆ alkylaminoC₁-C₆ alkyl, C₁-C₆ dialkylaminoC₁-C₆alkyl, arC₁-C₈ alkyl, substituted arC₁-C₈ alkyl wherein the substituenton the aralkyl group is one to five substituents independently selectedfrom halogen, nitro, amino, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆alkoxycarbonyl, hydroxyalkyl or aminosulfonyl; or

[0015] R₂ and R₃, together with the nitrogen to which they are attached,alternatively form an unsubstituted or substituted heteroalkyl groupselected from piperidinyl, piperazinyl or pyrrolidinyl, wherein thesubstituent is independently one or two substituents selected from C₁-C₆alkyl;

[0016] R₄ is selected from unsubstituted or substituted aryl, arC₁-C₈alkyl, C₃-C₈ cycloalkyl, or heteroaryl, where the substituents on thearyl, arC₁-C₈ alkyl, cycloalkyl or heteroaryl group are independentlyselected from one or more of halogen, nitro, amino, cyano, hydroxyalkyl,C₁-C₈ alkyl, C₁-C₈ alkoxy, hydroxy, C₁-C₄ alkylcarbonyl, C₁-C₈alkoxycarbonyl, fluorinated C₁-C₄ alkyl, fluorinated C₁-C₄ alkoxy orC₁-C₄ alkylsulfonyl;

[0017] Preferably, R₄ is selected from unsubstituted or substitutedaryl, arC₁-C₆ alkyl, C₃-C₆ cycloalkyl or heteroaryl, where thesubstituents on the aryl, aralkyl, cycloalkyl or heteroaryl group areindependently selected from one to three substituents selected fromhalogen, cyano, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxycarbonyl,fluorinated C₁-C₄ alkyl, fluorinated C₁-C₄ alkoxy or C₁-C₄alkylsulfonyl;

[0018] R₅ is selected from hydrogen or C₁-C₈alkyl; preferably, R₅ ishydrogen;

[0019] X is oxygen or sulfur; preferably, X is oxygen;

[0020] m is an integer selected from 0, 1, 2 or 3;

[0021] n is an integer selected from 2 or 3; and

[0022] p is an integer selected from 0 or 1; preferably, p is 1;

[0023] and pharmaceutically acceptable salts thereof.

[0024] In a preferred embodiment of the present invention:

[0025] A₁ is an L-amino acid selected from the group consisting ofalanine, arginine, cyclohexylalanine, glycine, proline,tetrahydroisoquinoline-3-COOH, and an unsubstituted or substitutedaromatic amino acid selected from the group consisting of phenylalanine,naphthylalanine, homophenylalanine, and O-methyl tyrosine, wherein thesubstituents on the aromatic amino acid are independently selected fromone to five of (preferably, one to three of) halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, hydroxy, C₁-C₄ alkoxycarbonyl, amino, amidino, guanidino,fluorinated C₁-C₄ alkyl, fluorinated C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl,C₁-C₄ alkylcarbonyl, cyano, aryl, heteroaryl, arC₁-C₄ alkyl, C₂-C₄alkenyl, alkynyl, or nitro;

[0026] A₂ is an L-amino acid selected from the group consisting ofalanine, β-alanine, arginine, citrulline, cysteine (optionallysubstituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl),2,4-diaminobutyric acid (optionally substituted with acyl, C₁-C₄ alkyl,aroyl, amidino, or MeC(NH)—), 2,3-diaminopropionic acid (optionallysubstituted with acyl, C₁-C₄ alkyl, aroyl, amidino, or MeC(NH)—),glutamine, glycine, lysine (optionally substituted with acyl, C₁-C₄alkyl, aroyl, MeC(NH)—), valine, methionine, serine (optionallysubstituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), homoserine(optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl),threonine (optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄alkyl), ornithine (optionally substituted with acyl, C₁-C₄ alkyl, aroyl,MeC(NH)—), and an unsubstituted or substituted aromatic amino acidselected from the group consisting of phenylalanine, heteroarylalanine,and histidine, wherein the substituents on the aromatic amino acid areindependently selected from one to five of (preferably, one to three of)halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, C₁-C₄ alkoxycarbonyl,amino, amidino, guanidino, fluorinated C₁-C₄ alkyl, fluorinated C₁-C₄alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylcarbonyl, cyano, aryl,heteroaryl, arC₁-C₄ alkyl, C₂-C₄ alkenyl, alkynyl, or nitro;

[0027] R₂ is selected from hydrogen or C₁-C₄ alkyl;

[0028] m is 1 and n is 2;

[0029] and all other variables are as defined previously;

[0030] and pharmaceutically acceptable salts thereof.

[0031] In a class of the invention:

[0032] A₁ is an L-amino acid selected from the group consisting ofalanine, arginine, cyclohexylalanine, glycine, proline, and anunsubstituted or substituted aromatic amino acid selected from the groupconsisting of phenylalanine, naphthylalanine, homophenylalanine, andO-methyl tyrosine, wherein the substituents on the aromatic amino acidare independently one to two substituents selected from halogen, C₁-C₄alkyl, C₁-C₄ alkoxy, hydroxy, C₁-C₄ alkoxycarbonyl, amino, amidino,guanidino, fluorinated C₁-C₄ alkyl, fluorinated C₁-C₄ alkoxy, C₁-C₄alkylsulfonyl, C₁-C₄ alkylcarbonyl, cyano, aryl, heteroaryl, arC₁-C₄alkyl, C₂-C₄ alkenyl, alkynyl, or nitro;

[0033] A₂ is an L-amino acid selected from the group consisting ofalanine, β-alanine, arginine, citrulline, cysteine (optionallysubstituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl),2,4-diaminobutyric acid (optionally substituted with acyl, C₁-C₄ alkyl,aroyl, amidino, or MeC(NH)—), 2,3-diaminopropionic acid (optionallysubstituted with acyl, C₁-C₄ alkyl, aroyl, amidino, or MeC(NH)—),glutamine, glycine, lysine (optionally substituted with acyl, C₁-C₄alkyl, aroyl, MeC(NH)—), valine, methionine, serine (optionallysubstituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), homoserine(optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl),threonine (optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄alkyl), ornithine (optionally substituted with acyl, C₁-C₄ alkyl, aroyl,MeC(NH)—), and an unsubstituted or substituted aromatic amino acidselected from the group consisting of phenylalanine, heteroarylalanine,and histidine, wherein the substituents on the aromatic amino acid areindependently one to two substituents selected from halogen, C₁-C₄alkyl, C₁-C₄ alkoxy, hydroxy, C₁-C₄ alkoxycarbonyl, amino, amidino,guanidino, fluorinated C₁-C₄ alkyl, fluorinated C₁-C₄ alkoxy, C₁-C₄alkylsulfonyl, C₁-C₄ alkylcarbonyl, cyano, aryl, heteroaryl, arC₁-C₄alkyl, C₂-C₄ alkenyl, alkynyl, or nitro;

[0034] R₁ is selected from dimethylamino, diethylamino,di-(n-propyl)amino,

[0035] Preferably, R₁ is:

[0036] R₂ is selected from hydrogen, methyl or ethyl;

[0037] R₃ is selected from 2-indanyl, phenyl, cyclohexylmethyl,cyclopentyl, pyridyl methyl, furanylmethyl, 2-(4-methyl-furanyl)methyl,thienylmethyl, diphenylmethyl, 4-imidazolylethyl,2-(4-N-methyl)imidazolylethyl, n-octyl, phenyl-n-propyl, aminoethyl,aminopropyl, amino-n-pentyl, dimethylaminoethyl,4-aminophenylsulfonylaminomethyl, acetamidineylethyl,2-N-pyrrolidinylethyl, N-ethoxycarbonylpiperidinyl, unsubstituted orsubstituted phenylethyl or unsubstituted or substituted benzyl whereinthe substituents on the phenylethyl or benzyl are independently one ortwo substituents selected from methyl, fluorine, chlorine, nitro,methoxy, methoxycarbonyl or hydroxymethyl; or

[0038] R₂ and R₃, together with the nitrogen to which they are attached,alternatively form a heteroalkyl group selected from piperidinyl, or4-(N-methyl)piperazinyl;

[0039] R₄ is selected from cyclohexyl, 2-naphthyl, phenylethyl,4-fluorophenylethyl, or unsubstituted or substituted phenyl, where thesubstituents on the phenyl are independently selected from one to twosubstituents selected from fluorine, chlorine, iodine, methyl, cyano, ortrifluoromethyl;

[0040] Preferably, R₄ is 2,6-dichlorophenyl or 2-methylphenyl;

[0041] and all other variables are as defined previously;

[0042] and pharmaceutically acceptable salts thereof.

[0043] In a subclass of the invention,

[0044] A₁ is selected from 3,4-Difluorophenylalanine or4-Chlorophenylalanine;

[0045] A₂ is selected from 2,4-Diaminobutyric acid or 4-Pyridylalanine;

[0046] R₂ is hydrogen;

[0047] R₃ is selected from benzyl or 2-aminoethyl;

[0048] and all other variables are as defined previously;

[0049] and pharmaceutically acceptable salts thereof.

[0050] Illustrative of the invention is a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and any of thecompounds described above. Illustrating the invention is apharmaceutical composition made by mixing any of the compounds describedabove and a pharmaceutically acceptable carrier. An illustration of theinvention is a process for making a pharmaceutical compositioncomprising mixing any of the compounds described above and apharmaceutically acceptable carrier.

[0051] An example of the invention is a method of treating a disorder(preferably, a platelet-mediated thrombotic disorder) selected fromarterial and/or venous thrombosis, acute myocardial infarction,reocclusion following thrombolytic therapy and/or angioplasty,inflammation, unstable angina, stroke, restenosis, atherosclerosis,ischemic conditions, hypertension, heart failure, arrhythmia,glomerulonephritis, osteoporosis, Angiogenesis related disorders,cancer, neurodegenerative disorders and a variety of vaso-occlusivedisorders in a subject in need thereof comprising administering to thesubject a therapeutically effective amount of any of the compounds orpharmaceutical compositions described above. In a preferred embodiment,the therapeutically effective amount of the compound is from about 0.1mg/kg/day to about 300 mg/kg/day.

[0052] Also included in the invention is the use of any of the compoundsdescribed above for the preparation of a medicament for a disorder(preferably, a platelet-mediated thrombotic disorder) selected fromarterial and/or venous thrombosis, acute myocardial infarction,reocclusion following thrombolytic therapy and/or angioplasty,inflammation, unstable angina, stroke, restenosis, atherosclerosis,ischemic conditions, hypertension, heart failure, arrhythmia,glomerulonephritis, osteoporosis, Angiogenesis related disorders,cancer, neurodegenerative disorders or a variety of vaso-occlusivedisorders in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0053] More particularly, the present invention is directed to compoundsof the following formula (I):

[0054] wherein A₁, A₂, R₁, R₂, R₃, R₄, R₅, X, m, n and p are aspreviously defined. In a particularly preferred embodiment, thecompounds have the formula

[0055] The compounds of the present invention are thrombin receptorantagonists and as such are useful in treating thrombosis, restenosis,hypertension, heart failure, arrhythmia, myocardial infarction,glomerulonephritis, reocclusion following thrombolytic therapy,reocclusion following angioplasty, inflammation, angina, stroke,atherosclerosis, ischemic conditions, a vaso-occlusive disorder,neurodegenerative disorders, Angiogenesis related disorders and cancer.These compounds are also useful as antithrombotics in conjunction withfibrinolytic therapy (e.g., t-PA or streptokinase).

[0056] In the compounds of formula (I), the amino acid residuescomprising the A₁ and A₂ substituents are attached to the adjacentmoiety according to standard nomenclature so that the amino-terminus(N-terminus) of the amino acid is drawn on the left and thecarboxy-terminus of the amino acid is drawn on the right. So, forexample, in Compound 1 in Table 1, where A₁ is 3,4-difluorophenylalanineand A₂ is Dbu (2,4-Diaminobutyric acid), the N-terminus of the3,4-difluorophenylalanine (A₁) is attached to the carbonyl group and thecarboxy-terminus of the 3,4-difluorophenylalanine (A₁) is attached tothe N-terminus of the A₂ substituent (Dbu), similarly, the N-terminus ofthe Dbu (A₂) is attached to the carboxy-terminus of the A₁ substituentand the carboxy-terminus of the Dbu (A₂) is attached to the N—R₂R₃group.

[0057] When a particular group is “substituted” (e.g., Phe, aryl,heteroalkyl, heteroaryl), that group may have one or more substituents,preferably from one to five substituents, more preferably from one tothree substituents, most preferably from one to two substituents,independently selected from the list of substituents.

[0058] Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenylC₁-C₆ alkylamidoC₁-C₆alkyl” substituentrefers to a group of the formula

[0059] The compounds of the present invention may also be present in theform of a pharmaceutically acceptable salt. The pharmaceuticallyacceptable salt generally takes a form in which the basic nitrogen isprotonated with an inorganic or organic acid. Representative organic orinorganic acids include hydrochloric, hydrobromic, hydriodic,perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic,lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic,mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic,oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic,cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic.

[0060] Where the compounds according to this invention have at least onechiral center, they may accordingly exist as enantiomers. Where thecompounds possess two or more chiral centers, they may additionallyexist as diastereomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention. Furthermore, some of the crystalline forms for the compoundsmay exist as polymorphs and as such are intended to be included in thepresent invention. In addition, some of the compounds may form solvateswith water (i.e., hydrates) or common organic solvents, and suchsolvates are also intended to be encompassed within the scope of thisinvention.

[0061] The term “subject” as used herein, refers to an animal,preferably a mammal, most preferably a human, who has been the object oftreatment, observation or experiment.

[0062] The term “therapeutically effective amount” as used herein, meansthat amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

[0063] As used herein, unless otherwise noted alkyl and alkoxy whetherused alone or as part of a substituent group, include straight andbranched chains having 1 to 8 carbon atoms, or any number within thisrange. For example, alkyl radicals include methyl, ethyl, propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyland 2-methylpentyl. Alkoxy radicals are oxygen ethers formed from thepreviously described straight or branched chain alkyl groups. Cycloalkylgroups contain 3 to 8 ring carbons and preferably 5 to 7 carbons.Similarly, alkenyl and alkynyl groups include straight and branchedchain alkenes and alkynes having 1 to 8 carbon atoms, or any numberwithin this range.

[0064] The term “aryl” as used herein refers to an unsubstituted orsubstituted aromatic group such as phenyl and naphthyl. The term “aroyl”refers to the group —C(O)-aryl.

[0065] The term “heteroalkyl” as used herein represents an unsubstitutedor substituted stable three to seven membered monocyclic saturated ringsystem which consists of carbon atoms and from one to three heteroatomsselected from N, O or S, and wherein the nitrogen or sulfur heteroatomsmay optionally be oxidized, and the nitrogen heteroatom may optionallybe quaternized. The heteroalkyl group may be attached at any heteroatomor carbon atom which results in the creation of a stable structure.Examples of such heteroalkyl groups include, but are not limited toazetidinyl, piperidinyl, pyrrolidinyl, piperazinyl, oxopiperazinyl,oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl,tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl,tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone and oxadiazolyl. Preferredheteroalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, azetidinyl and tetrahydrothiazolyl.

[0066] The term “heteroaryl” as used herein represents an unsubstitutedor substituted stable five or six membered monocyclic aromatic ringsystem or an unsubstituted or substituted nine or ten memberedbenzo-fused heteroaromatic ring system or bicyclic heteroaromatic ringsystem which consists of carbon atoms and from one to four heteroatomsselected from N, O or S, and wherein the nitrogen or sulfur heteroatomsmay optionally be oxidized, and the nitrogen heteroatom may optionallybe quaternized. The heteroaryl group may be attached at any heteroatomor carbon atom that results in the creation of a stable structure.Examples of heteroaryl groups include, but are not limited to pyridyl,pyridazinyl, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl,pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, benzimidazolyl,benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl,benzopyrazolyl, indolyl, benzothiazolyl, benzothiadiazolyl,benzotriazolyl adeninyl or quinolinyl. Prefered heteroaryl groupsinclude pyridyl, pyrrolyl, pyrazinyl, thiadiazolyl, pyrazolyl, thienyl,triazolyl and quinolinyl.

[0067] The term “aralkyl” means an alkyl group substituted with one, twoor three aryl groups (e.g., benzyl, phenylethyl, diphenylmethyl,triphenylmethyl). Similarly, the term “aralkoxy” indicates an alkoxygroup substituted with an aryl group (e.g., benzyloxy). The termaminoalkyl refers to an alkyl group substituted with an amino group(i.e., -alkyl-NH₂). The term “alkylamino” refers to an amino groupsubstituted with an alkyl group (i.e., —NH-alkyl). The term“dialkylamino” refers to an amino group which is disubstituted withalkyl groups wherein the alkyl groups can be the same or different(i.e., —N-[alkyl]₂).

[0068] The term “acyl” as used herein means an organic radical having 1to 6 carbon atoms (branched or straight chain) derived from an organicacid by removal of the hydroxyl group.

[0069] The term “oxo” refers to the group ═O.

[0070] The term “carbonyl” refers to the group C(O).

[0071] The term “halogen” shall include iodine, bromine, chlorine andfluorine.

[0072] The term “N(CH₂)₄” as used herein (e.g., in the Tables), refersto a pyrrolidinyl group having the structure

[0073] Similarly, “N(CH₂)₅”, “N(CH₂)₃”, “NCH₂S(CH₂)₂” and“N(CH₂)₂O(CH₂)₂” refer to

[0074] respectively.

[0075] Similarly “C₆H₁₁” and “C₅H₉” (or “c-C₆H₁₁” and “c-C₅H₉”) refer tocyclohexyl and cyclopentyl groups, respectively.

[0076] Whenever the term “alkyl” or “aryl” or either of their prefixroots appear in a name of a substituent (e.g., aralkyl, dialkylamino) itshall be interpreted as including those limitations given above for“alkyl” and “aryl.” Designated numbers of carbon atoms (e.g., C₁-C₆)shall refer independently to the number of carbon atoms in an alkyl orcycloalkyl moiety or to the alkyl portion of a larger substituent inwhich alkyl appears as its prefix root.

[0077] As used herein, the term “phosgene equivalent” represents theclass of carbonic acid derivatives which include 4-nitrophenylchloroformate, phosgene or “COCl₂,” phenyl chloroformate, triphosgene or“(CCl₃O)₂CO,” carbonyldiimidazole, diethyl carbonate or diphenylcarbonate.

[0078] It is intended that the definition of any substituent or variableat a particular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

[0079] As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.Accordingly, pharmaceutical compositions containing the compounds of thepresent invention as the active ingredient as well as methods ofpreparing the instant compounds are also part of the present invention.

[0080] Particularly preferred compounds of the present invention andtheir biological data are shown in Tables 1 and 2, following; the aminoacids bear the “L” absolute configuration unless denoted otherwise. TheTables contain IC₅₀ values (μM) of the compounds in a thrombin receptorbinding assay, and IC₅₀ values (μM) against platelet aggregationstimulated by thrombin. TABLE 1 6-Substituted BenzimidazolonePeptidomimetics

IC₅₀ (μM) Thr GFP Thr recptr Compd R₁ R₄ A₁ A₂NR₂R₃ Aggr^(a) Bdg^(b) 1CH₂N(CH₂)₄ 2,6-DiCl-Ph^(c) 3,4-DiF-Phe^(d) Dbu^(e)-NHBn 0.39 1.6 4CH₂NMe₂ 2-Me-Ph 3,4-DiF-Phe Dbu-NHBn 0.23 0.7 5 CH₂N(CH₂)₄ 2-Me-Ph3,4-DiF-Phe Dbu-NHBn 0.28 0.4 6 CH₂N(CH₂)₄ 4-F-Ph 3,4-DiF-Phe Dbu-NHBn 60.6 8 CH₂N(CH₂)₄ 4-F-Ph 3,4-DiF-Phe 4-PyrAla^(f)-NH(CH₂)₂NH₂ 5.8 0.5

[0081] TABLE 2 5-Substituted Benzimidazolone Peptidomimetics

IC₅₀ (μM) Thr GFP Thr Recptr Compd R₁ R₄ A₁ A₂NR₂R₃ Aggr^(a) Bdg^(b) 2CH₂N(CH₂)₄ 2-Me-Ph 3,4-DiF-Phe Dbu-NHBn 7 3 3 CH₂NMe₂ 2-Me-Ph3,4-DiF-Phe Dbu-NHBn 7.7 1.9 7 CH₂N(CH₂)₄ 2,6-DiCl-Ph 3,4-DiF-PheDbu-NHBn 5.5 1.7

[0082] The antagonists of the present invention may be prepared via aconvergent solution-phase synthesis by coupling an aminobenzimidazoloneintermediate AAG4 with a dipeptide amine AAG6 via a urea linkage asdescribed in the general Scheme AAGeneric. The appropriately nitrosubstituted benzimidazolone AAG1 (Scheme AAGeneric) was alkylated with asubstituted aralkyl or heteroaryl alkyl halide and a base such as sodiumhydride in a dipolar aprotic solvent such as DMF to give AAG2 as amixture of two regioisomers. Two isomers were separated by silica gelcolumn and then alkylated, with an aminoalkyl halide and a base such assodium hydride in a dipolar aprotic solvent such as DMF to give tworegioisomers AAG3, respectively. Reduction of nitro group in AAG3 in aclassical manner with for example iron and acetic acid or with a newermethod such as dimethyl hydrazine and iron to gave aminobenzimidazoloneintermediate AAG4.

[0083] Dipeptide amine AAG6 can be synthesized from the correspondingprotected amino acids using standard peptide coupling conditions. Thus,an Fmoc protected amino-acid (A₂) AAG5 (Scheme AAGeneric) was coupled toamine R₂R₃NH using a coupling agent, such as dicyclohexylcarbodiimide(DCC) or diisopropylcarbodiimide (DIC) and 1-hydroxybenzotriazole (HOBT)in a dipolar aprotic solvent such as DMF to give the amide. The amidewas then Fmoc deprotected with a dialkylamine in a dipolar aproticsolvent, such as diethylamine in acetonitrile. The resulting amine wascoupled to the second Fmoc protected amino-acid (A₁) in the same waywith a coupling agent, such as DIC and HOBT in a dipolar aprotic solventsuch as DMF to give the dipeptide. The dipeptide was then Fmocdeprotected as above with a dialkylamine in a dipolar aprotic solventsuch as acetonitrile to afford dipeptide amine AAG6.

[0084] Aminobenzimidazolone intermediate AAG4 was treated with aphosgene equivalent such as 4-nitrophenyl chloroformate, phosgene or“COCl₂,” phenyl chloroformate, triphosgene or “(CCl₃O)₂CO,”carbonyldiimidazole, diethyl carbonate or diphenyl carbonate and a basesuch as diisopropylethylamine in a solvent such as dichloromethane, andto this was then added dipeptide amine AAG6 to give a urea. Removal ofthe protecting group, if necessary, such as the Boc group with an acidsuch as trifluoroacetic acid from the side chain of dipeptide affordedfinal targets AAG7.

[0085] As a typical example of this convergent solution-phase method,Compound 1 may be synthesized as described in Scheme AA. Thus, treatmentof 5-nitrobenzimidazolone AA1 with 2,6-diCl-Bn-Br in the presence of NaHin DMF afforded two regioisomers AA2a and AA3a (ca. 1:1 ratio), whichwere then separated by flash column. A small amount of bis-alkylatedproduct was also obtained. The isolated AA3a was further alkylated with2-chloroethylpyrrolidine by using NaH as a base in DMF to give thedi-alkylated product, which was then subjected to nitro reduction withMe₂NNH₂/FeCl₃ to provide aminobenzimidazolone intermediate AA4. Couplingof N-α-Fmoc-N-γ-Boc-diaminobutyric acid (AA5) with benzyl amine in thepresence of DCC and HOBt was followed by de-protection of the Fmoc groupwith diethylamine. The resulting intermediate was coupled withFmoc-3,4-diF-Phe-OH using DIC/HOBt and treated with diethylamine to givedipeptide amine AA6. Urea formation between the dipeptide amine AA6 andaminobenzimidazolone intermediate AA4 in the presence of4-nitrophenylchloroformate was followed by de-protection of the Bocgroup with TFA to afford the target compound 1.

[0086] In an alternative approach to the targets, the preferredintermediate AA3 could be prepared via a regioselective method. Forexample, reductive alkylation of 4-nitro-1,2-phenylenediamine AB1 withone equivalent of 4-fluorobenzaldehyde in the presence of sodiumtriacetoxyborohydride gave mono-alkylated product AB2 which was thencyclized with N,N′-disuccinimidyl carbonate in acetonitrile to give AA3c(Scheme AB). By following the same procedure as described in Scheme AA,the target 6 was obtained from intermediate AA3c.

[0087] The side-chain amine in antagonists such as Compound 1 andCompound 8 may be converted to other functional groups such asacetamidine and guanidine by using standard procedures. For example, theacetamidine and guanidine groups can be introduced by treating theside-chain amine with S-2-naphthylmethyl thioacetimidate hydrobromideand 2-methyl-2-thiopseudourea, respectively.

[0088] The thioureidoindoles [when X is S, as in general formula (I)]may be prepared as described hereinafter. The aminobenzimidazolonesubstrate is reacted with thiocarbonyldiimidazole in a chlorinatedsolvent and then with the imidazole by-product filtered from thesolution. The solution can then be concentrated to afford theN-imidazolyl-N′-benzimidazolonyl-thioamide. This intermediate is thenreacted with a peptide amine in a polar, aprotic solvent with heating(from about 80° C. to about 100° C.) to afford theN-peptido-N′-benzimidazolonyl-thiourea product.

[0089] Amidobenzimidazolone targets [when p is 0 and X is O, as ingeneral formula (I)] may be prepared from a dipeptide amine AAG6 (SchemeAAGeneric) and a benzimidazolone carboxylic acid intermediate by usingstandard coupling conditions such as DCC/HOBt. The requiredbenzimidazolone carboxylic acid intermediates can be prepared by usingthe method as described for aminobenzimidazolone intermediate AAG4 inScheme AAGeneric from the appropriate benzimidazolone carboxylic acidesters.

[0090] The utility of the compounds to treat PAR-1 mediated disorders(e.g., thrombotic disorders) can be determined according to theprocedures described herein. The present invention therefore provides amethod of treating PAR-1 mediated disorders (e.g., thrombotic disorders)in a subject in need thereof which comprises administering any of thecompounds as defined herein in a quantity effective to treat PAR-1mediated disorders. The compound may be administered to a patient by anyconventional route of administration, including, but not limited to,intravenous, oral, subcutaneous, intramuscular, intradermal andparenteral.

[0091] The present invention also provides pharmaceutical compositionscomprising one or more compounds of this invention in association with apharmaceutically acceptable carrier.

[0092] To prepare the pharmaceutical compositions of this invention, oneor more compounds of formula (I) or salt thereof of the invention as theactive ingredient, is intimately admixed with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques, whichcarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral such asintramuscular. In preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. Thus, for liquid oralpreparations, such as, for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules, caplets,gelcaps and tablets, suitable carriers and additives include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. For parenterals, the carrier will usuallycomprise sterile water, though other ingredients, for example, forpurposes such as aiding solubility or for preservation, may be included.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Thepharmaceutical compositions herein will contain, per dosage unit, e.g.,tablet, capsule, powder, injection, teaspoonful and the like, an amountof the active ingredient necessary to deliver an effective dose asdescribed above. The pharmaceutical compositions herein will contain,per unit dosage unit, e.g., tablet, capsule, powder, injection,suppository, teaspoonful and the like, from about 0.03 mg/kg to about100 mg/kg (preferred from about 0.1 mg/kg to about 30 mg/kg) of acompound of the present invention and may be given at a dosage fromabout 0.1 mg/kg/day to about 300 mg/kg/day (preferred from about 1mg/kg/day to about 50 mg/kg/day). The dosages, however, may be varieddepending upon the requirement of the patients, the severity of thecondition being treated and the compound being employed. The use ofeither daily administration or post-periodic dosing may be employed.

[0093] Preferably these compositions are in unit dosage forms such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums and other pharmaceuticaldiluents, e.g. water, to form a solid preformulation compositioncontaining a homogeneous mixture of a compound of the present inventionor a pharmaceutically acceptable salt thereof. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective dosageforms such as tablets, pills and capsules. This solid preformulationcomposition is then subdivided into unit dosage forms of the typedescribed above containing from about 0.1 mg to about 500 mg of theactive ingredient of the present invention. The tablets or pills of thenovel composition can be coated or otherwise compounded to provide adosage form affording the advantage of prolonged action. For example,the tablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permits the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterial can be used for such enteric layers or coatings, such materialsincluding a number of polymeric acids with such materials as shellac,cetyl alcohol and cellulose acetate.

[0094] The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

[0095] Where the processes for the preparation of the compoundsaccording to the invention give rise to mixture of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their components enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-1-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

[0096] During any of the processes for preparation of the compounds ofthe present invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

[0097] The method of treating PAR-1 mediated disorders described in thepresent invention may also be carried out using a pharmaceuticalcomposition comprising any of the compounds as defined herein and apharmaceutically acceptable carrier. The pharmaceutical composition maycontain between about 0.01 mg to about 100 mg, preferably from about 5to about 50 mg, of the compound, and may be constituted into any formsuitable for the mode of administration selected. Carriers includenecessary and inert pharmaceutical excipients, including, but notlimited to, binders, suspending agents, lubricants, flavorants,sweeteners, preservatives, dyes, and coatings. Compositions suitable fororal administration include solid forms, such as pills, tablets,caplets, capsules (each including immediate release, timed release andsustained release formulations), granules, and powders, and liquidforms, such as solutions, syrups, elixirs, emulsions, and suspensions.Forms useful for parenteral administration include sterile solutions,emulsions and suspensions.

[0098] Advantageously, compounds of the present invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three or four times daily.Furthermore, compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal skin patches well known to those of ordinary skill in thatart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen.

[0099] For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

[0100] The liquid forms in suitably flavored suspending or dispersingagents such as the synthetic and natural gums, for example, tragacanth,acacia, methyl cellulose and the like. For parenteral administration,sterile suspensions and solutions are desired. Isotonic preparationswhich generally contain suitable preservatives are employed whenintravenous administration is desired.

[0101] The compound of the present invention can also be administered inthe form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine or phosphatidylcholines.

[0102] Compounds of the present invention may also be delivered by theuse of monoclonal antibodies as individual carriers to which thecompound molecules are coupled. The compounds of the present inventionmay also be coupled with soluble polymers as targetable drug carriers.Such polymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

[0103] Compounds of this invention may be administered in any of theforegoing compositions and according to dosage regimens established inthe art whenever treatment of PAR-1 mediated disorders is required.

[0104] The daily dosage of the products may be varied over a wide rangefrom about 0.01 mg to about 1,000 mg per adult human per day. For oraladministration, the compositions are preferably provided in the form oftablets containing about 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0,15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 mg of the active ingredientfor the symptomatic adjustment of the dosage to the patient to betreated. An effective amount of the drug is ordinarily supplied at adosage level of from about 0.01 mg/kg to about 100 mg/kg of body weightper day. Preferably, the range is from about 0.03 mg/kg to about 10mg/kg of body weight per day. The compounds may be administered on aregimen of about 1 time per day to about 4 times per day.

[0105] Optimal dosages to be administered may be readily determined bythose skilled in the art, and will vary with the particular compoundused, the mode of administration, the strength of the preparation, themode of administration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

[0106] Biology

[0107] The compounds of the present invention are thrombin receptor(PAR-1) antagonists. The compounds interrupt platelet activation inducedby thrombin's proteolytic cleavage of its platelet surface receptor, andthereby inhibit platelet aggregation. Such compounds are, therefore,useful in treating platelet-mediated thrombotic disorders (e.g.,arterial and venous thrombosis, acute myocardial infarction, reocclusionfollowing thrombolytic therapy and angioplasty, and a variety ofvaso-occlusive disorders) and other PAR-1 mediated disorders.

[0108] In Vitro Thrombin Receptor Binding Assay

[0109] CHRF membranes (Jones, Biochim. Biophys. Acta 1992, 1136, 272)are thawed from −70° C., centrifuged at maximum speed for 5 min, washedtwice with binding buffer (50 mM HEPES containing 5 mM MgCl₂ and 0.1%BSA), and re-suspended in binding buffer (25 μg/100 mL). 100 μL ofmembranes are added to the 24-Wallac plates and delivered to the Tomtechapparatus. In a typical experiment, 6 μL of samples (from a 125 μg/mLintermediary plate, 20% DMSO) and 44 μL buffer are delivered to theplates (final conc. of compounds is 3.7 μg/mL, 0.6% DMSO). Similarly, 6μL 20% DMSO and 44 μL buffer are delivered to both column 1 (NSB) andcolumn 12 (TB). 10 μL Ser-pFPhe-Har-Leu-Har-Lys-Tyr-NH₂ (721-40; 500 μMin deionized water) is added to column 1.50 μL tritiated 721-40(specific activity 46 Ci/mmol) is added to all the wells. The plates aremixed well for 20 seconds, incubated for 30 min, and then harvested with10 mM HEPES/138 mM NaCl using the Skatron harvester. The filters (GF/CBrandel FPXLR 296) are presoaked 3 h in 0.5% polyethylenimine inHEPES/0.1M N-acetylglucosamine) are set in saran wrap and dried for 3min in the microwave, and placed in sample bags (Wallac 1450-432). 4.5mL scintillation fluid (Wallac, Betaplate Scint 1205-440) is added. Thebags are sealed, placed in filter cassettes (Wallac 1450-104), andanalyzed on the microbeta counter.

[0110] In Vitro Inhibition of Thrombin-Induced Gel-Filtered PlateletAggregation Assay

[0111] The percentage of platelet aggregation is calculated as anincrease in light transmission of compound-treated platelet concentratevs. control-treated platelet concentrate. Human blood is obtained fromdrug free, normal donors in tubes containing 0.13M sodium citrate.Platelet rich plasma (PRP) is collected by centrifugation of whole bloodat 200×g for 10 min at 25° C. The PRP (5 mL) is gel filtered throughSepharose 2B (bed volume 50 mL), and the platelet count is adjusted to2×10⁷ platelets per sample. The following constituents are added to asiliconized cuvette: concentrated platelet filtrate and Tyrode's buffer(0.14M NaCl, 0.0027M KCl, 0.012M NaHCO₃, 0.76 mM Na₂HPO₄, 0.0055Mglucose, 2 mg/mL BSA and 5.0 mM HEPES @ pH 7.4) in an amount equal to350 μL, 50 μL of 20 mM calcium and 50 μL of the test compound.Aggregation is monitored in a BIODATA aggregometer for the 3 minfollowing the addition of agonist (thrombin 50 μL of 1 unit/mL).

[0112] Tables 1 and 2 show the biological activity of the compounds ofthe present invention. Tables 1 and 2 contain IC₅₀ values (μM) of thecompounds against platelet aggregation stimulated by thrombin and IC₅₀values (μM) in a thrombin receptor (PAR-1) binding assay.

EXAMPLES

[0113] General Procedures: Protected amino acids were purchased fromNovabiochem, Bachem Bioscience, Advanced ChemTech or SyntheTech. Allother chemicals were obtained from commercial suppliers and used withoutfurther purification. ¹H and ¹³C NMR spectra were recorded on a BrukerAC 300B (300 MHz proton) or a Bruker AM-400 (400 MHz proton)spectrometer with Me₄Si as an internal standard (s=singlet, d=doublet,t=triplet, br=broad). APCI-MS and ES-MS were recorded on a VG PlatformII mass spectrometer; methane was used for chemical ionization, unlessnoted otherwise. Accurate mass measurements were obtained by using a VGZAB 2-SE spectrometer in the FAB mode. TLC was performed with Whatman250-μm silica gel plates. Preparative TLC was performed with Analtech1000-μm silica gel GF plates. Flash column chromatography was conductedwith flash column silica gel (40-63 μm) and column chromatography wasconducted with standard silica gel. HPLC separations were carried out onthree Waters PrepPak® Cartridges (25×100 mm, Bondapak®D C18, 15-20 μm,125 Å) connected in series; detection was at 254 nm on a Waters 486 UVdetector. Analytical HPLC was carried out on a Supelcosil ABZ+PLUScolumn (5 cm×2.1 mm), with detection at 254 nm on a Hewlett Packard 1100UV detector. Microanalysis was performed by Robertson MicrolitLaboratories, Inc.

[0114] In the examples and throughout this application, the followingabbreviations have the meanings recited hereinafter: Ac Acetyl ACNAcetonitrile Bn Benzyl Boc t-Butoxycarbonyl DCC1,3-Dicyclohexylcarbodiimide DCM Dichloromethane DICDiisopropylcarbodiimide DIEA Diisopropylethylamine DMAP4-Dimethylaminopyridine DMF N,N-Dimethylformamide Et Ethyl Fmoc9-Fluorenylmethoxycarbonyl h Hour HBTU2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphateHOAc Acetic acid HOBT Hydroxybenzotriazole Me Methyl min Minute rt roomtemperature THF Tetrahydrofuran TFA Trifluoroacetic acid

Example 1 Synthesis of Compound 1 (Scheme AA) Benzenepropanamide,N-[(1S)-3-amino-1-[[(phenylmethyl)amino]carbonyl]propyl]-α-[[[[3-(2,6-dichlorophenyl)methyl]-2,3-dihydro-2-oxo-1-[2-(1-pyrrolidinyl)ethyl]-1H-benzimidazol-5-yl]amino]carbonyl]amino]-3,4-difluoro-,(αS)-(1)

[0115] 5-Nitroimidazolone AA1 (1.44 g, 8.04 mm) in dry DMF (20 mL) underargon was cooled to about 0° C. and 75% NaH oil dispersion (0.284 g,8.86 mm) was added portionwise and stirred for about 5 min.2,6-Dichlorobenzylbromide (1.92 g, 8.0 mm) dissolved in dry DMF (20 mL)was added over about 5 min and the reaction was stirred at about 0° C.for about 30 min and then at about rt for about 3 h. The solution wasadded slowly to vigorously stirring water (700 mL) and after about 1 h,a white solid was filtered (2.38 g) that contained a mixture of AA2a andAA3a (ca. 1:1 ratio). A portion (1.5 g) was purified by flash columnchromatography using DCM:ethyl acetate (2:1) to give pure AA2a and AA3a.A sample of AA3a (105 mg, 0.30 mm) was dissolved in dry DMF (6 mL), 75%NaH (30 mg, 0.94 mm) was added and the mixture was stirred for aboutseveral min at about rt. 2-chloroethylpyrrolidine hydrochloride (103 mg,0.60 mm) was added and the mixture was stirred at about 50° C. for about2 h. The reaction was cooled and partitioned betweenchloroform:2-propanol (10:1) and water; the organic solution was washedtwice with water, once with brine, dried (K₂CO₃) and evaporated in vacuoto a light yellow solid (130 mg). This solid was dissolved in MeOH (8.0mL) and ferric chloride hexahydrate (30 mg, 0.11 mm), charcoal (60 mg, 5mm) and 1,1 dimethyl hydrazine (1.5 g, 25 mm) were added and thereaction was refluxed for about 3 h. The solution was cooled to aboutrt, filtered through dicalite and the filtrate was evaporated in vacuoto a clear oil. The oil was dissolved in 1N HCl (25 mL) and washed twicewith ethyl ether. The acid was made alkaline with dilute NaOH andextracted with DCM, which was washed twice with sodium bicarbonatesolution, once with brine, dried (K₂CO₃) and evaporated in vacuo to givesolid AA4 (100 mg). Fmoc-α-N-Boc-γ-N-diaminobutyric acid AA5 (10.8 g,24.5 mmol) was stirred in ACN (300 mL) under argon as HOBT (3.75 g, 24.4mmol) was added, followed by benzylamine (2.6 g, 24.3 mmol). DCC (10.4g, 48.7 mmol) was also then added and the reaction was stirred at aboutrt for about 3 h, whereupon a white solid was filtered and washed withcold ACN (14.4 g). The solid was stirred in ACN (500 mL) containingdiethyl amine (25 mL) for about 2 h and a small quantity of solid wasfiltered; the filtrate was evaporated in vacuo to an oil, which wastriturated three times with hexane (400 mL each) to white solid. Thesolid was dissolved in ACN (400 mL), then HOBT (2.9 g, 19.1 mm) andFmoc-3,4 difluorophenylalanine (8.1 g, 19.1 mmol) were added, followedby DIC (4.81 g, 38.2 mmol) and stirred at about rt for about 16 h. Thereaction was cooled in an ice bath and a white solid was filtered thenwashed with cold ACN. The solid was stirred in ACN (350 mL) containingdiethylamine (35 mL) for about 5 h and evaporated in vacuo to a whitesolid. The solid was triturated three times with hexane, dissolved inchloroform (250 mL), dried (Na₂SO₄) and evaporated in vacuo to a whitesolid AA6 (8.0 g). 4-Nitrophenyl chloroformate (20 mg, 0.10 mm) in DCM(5 mL) was cooled to about −20° C. and AA4 (40 mg, 0.10 mm) anddiisopropylethylamine (13 mg, 0.10 mm) in DCM (1.5 mL) were added andstirred for about 30 min. The amine AA6 (50 mg, 0.10 mm) anddiisopropylethylamine (13 mg, 0.10 mm) in DCM (2.0 mL) were added to thesolution at about −20° C. and stirred at about −20° C. for about 30 min.The mixture was then allowed to come to about rt, whereupon the reactionwas stirred for about another 16 h. A light yellow solid was filtered(45 mg) and then stirred into DCM (7 mL) containing anisole (10 mg) asTFA (3.0 mL) was added under argon. The reaction was stirred at about rtfor about 1.5 h and then evaporated in vacuo to an oil, which wastriturated three times with ethyl ether to give Compound 1, a whitesolid, as its trifluoroacetate salt. ¹H NMR (CD₃OD) δ 1.9-2.2 (m, 6H),2.9-3.1 (m, 3H), 3.1-3.3 (m, 4H), 3.6 (dd, 2H), 3.8 (m, 2H), 4.25 (dd,2H), 4.35 (s, 2H), 4.45 (dd, 2H), 5.32 (s, 2H), 7.0-7.5 (m, aromatics).ES-MS m/z 821 (MH⁺). FAB-HRMS calcd for C₄₁H₄₄Cl₂F₂N₈O₄+H⁺: 821.2909,found 821.2918.

Example 2 Synthesis of Compound 6 (Scheme AB) Benzenepropanamide,N-[(1S)-3-amino-1-[[(phenylmethyl)amino]carbonyl]propyl]-α-[[[[3-(4-fluorophenyl)methyl]-2,3-dihydro-2-oxo-1-[2-(1-pyrrolidinyl)ethyl]-1H-benzimidazol-5-yl]amino]carbonyl]amino]-3,4-difluoro-,(αS)-(6)

[0116] 4-Nitro-1,2-phenylene diamine (AB1, 2.00 g, 13.0 mmml) wassuspended in DCE (100 mL) followed by the addition of4-fluorobenzaldehyde (1.39 mL, 13.0 mmol), acetic acid (0.74 mL, 13.0mmol), and sodium triacetoxyborohydride (5.51 g, 26.0 mmol). Reactionwas stirred at ambient temperature for 24 h. Additional sodiumtriacetoxyborohydride (5.51 g, 26.0 mm) was added and the reaction wasstirred at ambient temperature for 24 h. The reaction mixture wasdiluted with EtOAc (175 mL), washed with H₂O (2×50 mL), brine (50 mL),dried (Na₂SO₄), and evaporated in vacuo to give a solid. The crudeproduct was purified by column chromatography (silica gel, 20% EtOAc/80%Hexane to 40% EtOAc/60% Hexane) to afford AB2 (1.42 g, 42%). To asolution of AB2 (1.39 g, 5.3 mmol) in acetonitrile (80 mL) was addedN,N′-disuccinimidyl carbomate (1.36 g, 5.3 mmol) in acetonitrile (80 mL)and the mixture was stirred at 75° C. After 24 h, additionalN,N′-disuccinimidyl carbonate (1.36 g, 5.3 mmol) was added and thereaction mixture stirred at 75° C. for another 24 h. The reaction wasstill not complete and additional N,N′-disuccinimidyl carbonate (1.36 g,5.3 mm) was added. The stirring was continued at 75° C. for 4 h, andthen the reaction mixture was evaporated in vacuo to give a solid. Thecrude product was purified by column chromatography (silica gel-30%EtOAc/70% Hexane to 50% EtOAc/50% Hexane) to afford AA3c (0.95 g, 62%).¹H NMR (DMSO) δ 5.13 (s, CH₂), 7.16-7.21 (m, 3H, H-11, H-13, and H-3),7.39-7.44 (m, 2H, H-10 and H-13, 7.97-8.01 (m, 2H, H-4 and H-5), 11.76(s, NH). To a solution of AA3c (0.50 g, 1.7 mmol) in dry DMF (24 ml) wasadded 60% NaH (0.20 g, 5.1 mm) and the mixture was stirred at rt forseveral min. 2-Chloroethylpyrrolidine hydrochloride (0.57 g, 3.4 mmol)was added and the mixture was stirred at about 50° C. overnight. Thereaction was cooled to rt and additional 60% NaH (32.0 mg, 0.85 mmol)and 2-chloroethylpyrrolidine hydrochloride (57.8 mg, 0.34 mmol) wasadded and the mixture was stirred at about 50° C. for 5 h. The reactionwas cooled and partitioned between chloroform:2-propanol (10:1) andwater; the organic solution was washed twice with water, twice withbrine, dried (K₂CO₃) and evaporated in vacuo to give a light yellowsolid (0.72 g). The solid (0.70 g, 1.8 mmol) was dissolved in MeOH (50mL) and ferric chloride hexahydrate (0.19 g, 0.70 mmol), charcoal, (0.39g) and 1,1-dimethyl hydrazine (12.2 mL, 160 mmol) were added and thereaction was refluxed for 2 h. The solution was cooled to rt, filteredthrough celite and the filtrate was evaporated in vacuo to give an oil.The oil was dissolved in 1 N HCl (150 mL) and washed twice with ether.The acid was basified with aqueous NaOH, extracted with DCM, which waswashed twice with sodium bicarbonate solution, twice with brine, dried(K₂CO₂) and evaporated in vacuo to give solid AB3 (0.39 g).4-Nitrophenyl chloroformate (0.028 g, 0.14 mmol) in DCM (5 mL) wascooled to about −20° C. and AB3 (50 mg, 0.14 mmol) anddiisopropylethylamine (18 mg, 0.14 mmol) in DCM (1.5 mL) were added andstirred for 2 h. The amine AA6 (0.079 g, 0.14 mmol) anddiisopropylethylamine (18 mg, 0.14 mmol) in DCM (2.0 mL) were added tothe solution at about −20° C. and stirred at about −20° C. for 1 h. Themixture was then allowed to warm up to rt, whereupon the reaction wasstirred for about 18 h. A light yellow solid was collected by filtrationand then treated with 30% TFA/DCM/1% anisole (8 mL) under N₂. Thereaction was stirred at rt for 1 h and was then blown down with N₂ to anoil, which was triturated four times with ethyl ether to give compound6, a white solid, as its trifluoroacetate salt. ¹H NMR (CD₃OD) δ1.95-2.20 (m, 6H), 2.96-3.61 (m, 11H), 4.29-4.33 (m, 4H), 4.47 (dd, 2H),5.01 (d, 2H), 6.96-7.36 (m, aromatics). ES-MS m/z 771 (MH⁺).

Example 3

[0117] As a specific embodiment of an oral composition, 100 mg of theCompound 1 of Example 1 is formulated with sufficient finely dividedlactose to provide a total amount of about 580 mg to about 590 mg tofill a size 0 hard gel capsule.

[0118] While the foregoing specification teaches the principles of thepresent invention, with examples provided for the purpose ofillustration, it will be understood that the practice of the inventionencompasses all of the usual variations, adaptations and/ormodifications as come within the scope of the following claims and theirequivalents.

1 1 1 7 PRT Artificial Sequence is an artifical antagonist for PAR1receptor 1 Ser Xaa Xaa Leu Xaa Lys Tyr 1 5

What is claimed is:
 1. A compound of the following formula (I):

wherein: A₁ and A₂ are each independently a D- or L-amino acid selected from the group consisting of alanine, β-alanine, arginine, homoarginine, cyclohexylalanine, citrulline, cysteine (optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), 2,4-diaminobutyric acid (optionally substituted with acyl, C₁-C₄ alkyl, aroyl, amidino, or MeC(NH)—), 2,3 diaminopropionic acid (optionally substituted with acyl, C₁-C₄ alkyl, aroyl, amidino, or MeC(NH)—), glutamine, glycine, indanylglycine, lysine (optionally substituted with acyl, C₁-C₄ alkyl, aroyl, MeC(NH)—), valine, methionine, proline, serine (optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), homoserine (optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), tetrahydroisoquinoline-3-COOH, threonine (optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), ornithine (optionally substituted with acyl, C₁-C₄ alkyl, aroyl, MeC(NH)—), and an unsubstituted or substituted aromatic amino acid selected from the group consisting of phenylalanine, heteroarylalanine, naphthylalanine, homophenylalanine, histidine, tryptophan, tyrosine, arylglycine, heteroarylglycine, aryl-β-alanine, and heteroaryl-β-alanine wherein the substituents on the aromatic amino acid are independently selected from one or more of halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, C₁-C₄ alkoxycarbonyl, amino, amidino, guanidino, fluorinated C₁-C₄ alkyl, fluorinated C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylcarbonyl, cyano, aryl, heteroaryl, arC₁-C₄ alkyl, C₂-C₄ alkenyl, alkynyl, or nitro; R₁ is selected from amino, C₁-C₈ alkylamino, C₁-C₈ dialkylamino, arylamino, arC₁-C₈ alkylamino, C₃-C₈ cycloalkylamino, heteroalkylC₁-C₈ alkylamino, heteroalkylC₁-C₈ alkyl-N-methylamino, C₁-C₈ dialkylaminoC₁-C₈ alkylamino, —N(C₁-C₈alkyl)-C₁-C₈ alkyl-N(C₁-C₈alkyl)₂, N(C₁-C₈ alkyl)(C₁-C₈ alkenyl), —N(C₁-C₈alkyl)(C₃-C₈cycloalkyl), heteroalkyl or substituted heteroalkyl wherein the substituent on the heteroalkyl is selected from oxo, amino, C₁-C₈ alkoxyC₁-C₈ alkyl, C₁-C₈ alkylamino or C₁-C₈ dialkylamino; R₂ and R₃ are each independently selected from hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₈ alkyl, aryl, heteroalkyl, substituted heteroalkyl (wherein the substituent on the heteroalkyl is one or more substituents independently selected from C₁-C₈ alkoxycarbonyl, C₁-C₈ alkyl, or C₁-C₄ alkylcarbonyl), heteroalkylC₁-C₈ alkyl, indanyl, acetamidinoC₁-C₈ alkyl, aminoC₁-C₈ alkyl, C₁-C₈ alkylaminoC₁-C₈ alkyl, C₁-C₈ dialkylaminoC₁-C₈ alkyl, unsubstituted or substituted heteroarylC₁-C₈ alkyl or unsubstituted or substituted arC₁-C₈ alkyl, wherein the substituent on the aralkyl or heteroarylalkyl group is one or more substituents independently selected from halogen, nitro, amino, C₁-C₈ alkyl, C₁-C₈ alkoxy, hydroxy, cyano, C₁-C₄ alkylcarbonyl, C₁-C₈ alkoxycarbonyl, hydroxyC₁-C₈ alkyl or aminosulfonyl; or R₂ and R₃, together with the nitrogen to which they are attached, alternatively form an unsubstituted or substituted heteroalkyl group selected from piperidinyl, piperazinyl, morpholinyl or pyrrolidinyl, wherein the substituent is one or more substituents independently selected from C₁-C₈ alkyl C₁-C₈ alkoxycarbonyl or C₁-C₄ alkylcarbonyl; R₄ is selected from unsubstituted or substituted aryl, arC₁-C₈ alkyl, C₃-C₈ cycloalkyl, or heteroaryl, where the substituents on the aryl, arC₁-C₈ alkyl, cycloalkyl or heteroaryl group are independently selected from one or more of halogen, nitro, amino, cyano, hydroxyalkyl, C₁-C₈ alkyl, C₁-C₈ alkoxy, hydroxy, C₁-C₄ alkylcarbonyl, C₁-C₈ alkoxycarbonyl, fluorinated C₁-C₄ alkyl, fluorinated C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl; R₅ is selected from hydrogen or C₁-C₈ alkyl; X is oxygen or sulfur; m is an integer selected from 0, 1, 2 or 3; n is an integer selected from 2 or 3; and p is an integer selected from 0 or 1; and pharmaceutically acceptable salts thereof.
 2. The compound of claim 1, wherein: A₁ and A₂ are each independently an L-amino acid selected from the group consisting of alanine, β-alanine, arginine, homoarginine, cyclohexylalanine, citrulline, cysteine (optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), 2,4-diaminobutyric acid (optionally substituted with acyl, C₁-C₄ alkyl, aroyl, amidino, or MeC(NH)—), 2,3 diaminopropionic acid (optionally substituted with acyl, C₁-C₄ alkyl, aroyl, amidino, or MeC(NH)—), glutamine, glycine, indanylglycine, lysine (optionally substituted with acyl, C₁-C₄ alkyl, aroyl, MeC(NH)—), valine, methionine, proline, serine (optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), homoserine (optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), tetrahydroisoquinoline-3-COOH, threonine (optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), ornithine (optionally substituted with acyl, C₁-C₄ alkyl, aroyl, MeC(NH)—), and an unsubstituted or substituted aromatic amino acid selected from the group consisting of phenylalanine, heteroarylalanine, naphthylalanine, homophenylalanine, histidine, tryptophan, tyrosine, arylglycine, heteroarylglycine, aryl-β-alanine, and heteroaryl-β-alanine wherein the substituents on the aromatic amino acid are independently selected from one or more of halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, C₁-C₄ alkoxycarbonyl, amino, amidino, guanidino, fluorinated C₁-C₄ alkyl, fluorinated C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylcarbonyl, cyano, aryl, heteroaryl, arC₁-C₄ alkyl, C₂-C₄ alkenyl, alkynyl, or nitro; R₁ is selected from amino, C₁-C₆ alkylamino, C₁-C₆ dialkylamino, arylamino, arC₁-C₆ alkylamino, heteroalkylC₁-C₆ alkylamino, —N(C₁-C₆alkyl)-C₁-C₆ alkyl-N(C₁-C₆alkyl)₂, heteroalkyl or substituted heteroalkyl wherein the substituent on the heteroalkyl is selected from oxo, amino, C₁-C₆alkoxyC₁-C₆ alkyl, C₁-C₆ alkylamino or C₁-C₆ dialkylamino; R₂ is selected from hydrogen or C₁-C₆ alkyl; R₃ is selected from C₁-C₈ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkylC₁-C₆ alkyl, aryl, heteroarylC₁-C₆ alkyl, substituted heteroarylC₁-C₆alkyl wherein the substituent is C₁-C₄ alkyl, heteroalkyl, heteroalkylC₁-C₆ alkyl, indanyl, acetamidinoC₁-C₆ alkyl, aminoC₁-C₆ alkyl, C₁-C₆alkylaminoC₁-C₆ alkyl, C₁-C₆ dialkylaminoC₁-C₆ alkyl, arC₁-C₈alkyl, substituted arC₁-C₈ alkyl wherein the substituent on the aralkyl group is one to five substituents independently selected from halogen, nitro, amino, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxycarbonyl, hydroxyalkyl or aminosulfonyl; R₂ and R₃, together with the nitrogen to which they are attached, alternatively form an unsubstituted or substituted heteroalkyl group selected from piperidinyl, piperazinyl or pyrrolidinyl, wherein the substituent is independently one or two substituents selected from C₁-C₆ alkyl; R₄ is selected from unsubstituted or substituted aryl, arC₁-C₆ alkyl, C₃-C₆ cycloalkyl or heteroaryl, where the substituents on the aryl, aralkyl, cycloalkyl or heteroaryl group are independently selected from one to three substituents selected from halogen, cyano, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄alkoxycarbonyl, fluorinated C₁-C₄ alkyl, fluorinated C₁-C₄ alkoxy or C₁-C₄alkylsulfonyl; R₅ is hydrogen; X is oxygen; and p is 1; and pharmaceutically acceptable salts thereof.
 3. The compound of claim 2, wherein: A₁ is an L-amino acid selected from the group consisting of alanine, arginine, cyclohexylalanine, glycine, proline, tetrahydroisoquinoline-3-COOH, and an unsubstituted or substituted aromatic amino acid selected from the group consisting of phenylalanine, naphthylalanine, homophenylalanine, and O-methyl tyrosine, wherein the substituents on the aromatic amino acid are independently selected from one to five of halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, C₁-C₄ alkoxycarbonyl, amino, amidino, guanidino, fluorinated C₁-C₄ alkyl, fluorinated C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylcarbonyl, cyano, aryl, heteroaryl, arC₁-C₄ alkyl, C₂-C₄ alkenyl, alkynyl, or nitro; A₂ is an L-amino acid selected from the group consisting of alanine, β-alanine, arginine, citrulline, cysteine (optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), 2,4-diaminobutyric acid (optionally substituted with acyl, C₁-C₄ alkyl, aroyl, amidino, or MeC(NH)—), 2,3-diaminopropionic acid (optionally substituted with acyl, C₁-C₄ alkyl, aroyl, amidino, or MeC(NH)—), glutamine, glycine, lysine (optionally substituted with acyl, C₁-C₄ alkyl, aroyl, MeC(NH)—), valine, methionine, serine (optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), homoserine (optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), threonine (optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), ornithine (optionally substituted with acyl, C₁-C₄ alkyl, aroyl, MeC(NH)—), and an unsubstituted or substituted aromatic amino acid selected from the group consisting of phenylalanine, heteroarylalanine, and histidine, wherein the substituents on the aromatic amino acid are independently selected from one to five of halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, C₁-C₄ alkoxycarbonyl, amino, amidino, guanidino, fluorinated C₁-C₄ alkyl, fluorinated C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylcarbonyl, cyano, aryl, heteroaryl, arC₁-C₄ alkyl, C₂-C₄ alkenyl, alkynyl, or nitro; R₂ is selected from hydrogen or C₁-C₄ alkyl; and m is 1 and n is 2; and pharmaceutically acceptable salts thereof.
 4. The compound of claim 3, wherein: A₁ is an L-amino acid selected from the group consisting of alanine, arginine, cyclohexylalanine, glycine, proline, and an unsubstituted or substituted aromatic amino acid selected from the group consisting of phenylalanine, naphthylalanine, homophenylalanine, and O-methyl tyrosine, wherein the substituents on the aromatic amino acid are independently one to two substituents selected from halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, C₁-C₄ alkoxycarbonyl, amino, amidino, guanidino, fluorinated C₁-C₄ alkyl, fluorinated C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylcarbonyl, cyano, aryl, heteroaryl, arC₁-C₄ alkyl, C₂-C₄ alkenyl, alkynyl, or nitro; A₂ is an L-amino acid selected from the group consisting of alanine, β-alanine, arginine, citrulline, cysteine (optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), 2,4-diaminobutyric acid (optionally substituted with acyl, C₁-C₄ alkyl, aroyl, amidino, or MeC(NH)—), 2,3-diaminopropionic acid (optionally substituted with acyl, C₁-C₄ alkyl, aroyl, amidino, or MeC(NH)—), glutamine, glycine, lysine (optionally substituted with acyl, C₁-C₄ alkyl, aroyl, MeC(NH)—), valine, methionine, serine (optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), homoserine (optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), threonine (optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), ornithine (optionally substituted with acyl, C₁-C₄ alkyl, aroyl, MeC(NH)—), and an unsubstituted or substituted aromatic amino acid selected from the group consisting of phenylalanine, heteroarylalanine, and histidine, wherein the substituents on the aromatic amino acid are independently one to two substituents selected from halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, C₁-C₄ alkoxycarbonyl, amino, amidino, guanidino, fluorinated C₁-C₄ alkyl, fluorinated C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylcarbonyl, cyano, aryl, heteroaryl, arC₁-C₄ alkyl, C₂-C₄ alkenyl, alkynyl, or nitro; R₁ is selected from dimethylamino, diethylamino, di-(n-propyl)amino,

R₂ is selected from hydrogen, methyl or ethyl; R₃ is selected from 2-indanyl, phenyl, cyclohexylmethyl, cyclopentyl, pyridylmethyl, furanylmethyl, 2-(4-methyl-furanyl)methyl, thienylmethyl, diphenylmethyl, 4-imidazolylethyl, 2-(4-N-methyl)imidazolylethyl, n-octyl, phenyl-n-propyl, aminoethyl, aminopropyl, amino-n-pentyl, dimethylaminoethyl, 4-aminophenylsulfonylaminomethyl, acetamidineylethyl, 2-N-pyrrolidinylethyl, N-ethoxycarbonylpiperidinyl, unsubstituted or substituted phenylethyl or unsubstituted or substituted benzyl wherein the substituents on the phenylethyl or benzyl are independently one or two substituents selected from methyl, fluorine, chlorine, nitro, methoxy, methoxycarbonyl or hydroxymethyl; or R₂ and R₃, together with the nitrogen to which they are attached, alternatively form a heteroalkyl group selected from piperidinyl, or 4-(N-methyl)piperazinyl; and R₄ is selected from cyclohexyl, 2-naphthyl, phenylethyl, 4-fluorophenylethyl or unsubstituted or substituted phenyl, where the substituents on the phenyl are independently selected from one to two substituents selected from fluorine, chlorine, iodine, methyl, cyano or trifluoromethyl; and pharmaceutically acceptable salts thereof.
 5. The compound of claim 4, wherein: R₁ is

and pharmaceutically acceptable salts thereof.
 6. The compound of claim 5, wherein: R₄ is selected from

and pharmaceutically acceptable salts thereof.
 7. The compound of claim 6, wherein: A₁ is selected from 3,4-Difluorophenylalanine or 4-Chlorophenylalanine; A₂ is selected from 2,4-Diaminobutyric acid or 4-Pyridylalanine; R₂ is hydrogen; and R₃ is selected from benzyl or 2-aminoethyl; and pharmaceutically acceptable salts thereof.
 8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim
 1. 9. A pharmaceutical composition made by mixing a compound of claim 1 and a pharmaceutically acceptable carrier.
 10. A process for making a pharmaceutical composition comprising mixing a compound of claim 1 and a pharmaceutically acceptable carrier.
 11. A method of treating a condition selected from the group consisting of thrombosis, restenosis, hypertension, heart failure, arrhythmia, myocardial infarction, glomerulonephritis, reocclusion following thrombolytic therapy, reocclusion following angioplasty, inflammation, angina, stroke, atherosclerosis, ischemic conditions, a vaso-occlusive disorder, neurodegenerative disorders, Angiogenesis related disorders and cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of claim
 1. 12. The method of claim 11, wherein the therapeutically effective amount of the compound is from about 0.1 mg/kg/day to about 300 mg/kg/day.
 13. A method of treating a condition selected from the group consisting of thrombosis, restenosis, hypertension, heart failure, arrhythmia, myocardial infarction, glomerulonephritis, reocclusion following thrombolytic therapy, reocclusion following angioplasty, inflammation, angina, stroke, atherosclerosis, ischemic conditions, a vaso-occlusive disorder, neurodegenerative disorders, Angiogenesis related disorders and cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the composition of claim
 8. 14. The method of claim 13, wherein the therapeutically effective amount of the compound is from about 0.1 mg/kg/day to about 300 mg/kg/day.
 15. A method of inhibiting platelet aggregation in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of claim
 1. 16. The method of claim 15, wherein the therapeutically effective amount of the compound is from about 0.1 mg/kg/day to about 300 mg/kg/day.
 17. A method of inhibiting platelet aggregation in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the composition of claim
 8. 18. The method of claim 17, wherein the therapeutically effective amount of the compound is from about 0.1 mg/kg/day to about 300 mg/kg/day.
 19. A method of treating a condition mediated by thrombin receptor (PAR-1) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of claim
 1. 20. The method of claim 19, wherein the therapeutically effective amount of the compound is from about 0.1 mg/kg/day to about 300 mg/kg/day.
 21. A method of treating a condition mediated by thrombin receptor (PAR-1) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the composition of claim
 8. 22. The method of claim 21, wherein the therapeutically effective amount of the compound is from about 0.1 mg/kg/day to about 300 mg/kg/day.
 23. A process for preparing a compound of the formula (II):

wherein: A₁ and A₂ are each independently a D- or L-amino acid selected from the group consisting of alanine, β-alanine, arginine, homoarginine, cyclohexylalanine, citrulline, cysteine (optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), 2,4-diaminobutyric acid (optionally substituted with acyl, C₁-C₄ alkyl, aroyl, amidino, or MeC(NH)—), 2,3 diaminopropionic acid (optionally substituted with acyl, C₁-C₄ alkyl, aroyl, amidino, or MeC(NH)—), glutamine, glycine, indanylglycine, lysine (optionally substituted with acyl, C₁-C₄ alkyl, aroyl, MeC(NH)—), valine, methionine, proline, serine (optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), homoserine (optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), tetrahydroisoquinoline-3-COOH, threonine (optionally substituted with C₁-C₄ alkyl, aryl, or arC₁-C₄ alkyl), ornithine (optionally substituted with acyl, C₁-C₄ alkyl, aroyl, MeC(NH)—), and an unsubstituted or substituted aromatic amino acid selected from the group consisting of phenylalanine, heteroarylalanine, naphthylalanine, homophenylalanine, histidine, tryptophan, tyrosine, arylglycine, heteroarylglycine, aryl-β-alanine, and heteroaryl-β-alanine wherein the substituents on the aromatic amino acid are independently selected from one or more of halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, C₁-C₄ alkoxycarbonyl, amino, amidino, guanidino, fluorinated C₁-C₄ alkyl, fluorinated C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylcarbonyl, cyano, aryl, heteroaryl, arC₁-C₄ alkyl, C₂-C₄ alkenyl, alkynyl, or nitro; R₁ is selected from amino, C₁-C₈ alkylamino, C₁-C₈ dialkylamino, arylamino, arC₁-C₈ alkylamino, C₃-C₈ cycloalkylamino, heteroalkylC₁-C₈ alkylamino, heteroalkylC₁-C₈ alkyl-N-methylamino, C₁-C₈ dialkylaminoC₁-C₈ alkylamino, —N(C₁-C₈alkyl)-C₁-C₈ alkyl-N(C₁-C₈alkyl)₂, N(C₁-C₈ alkyl)(C₁-C₈ alkenyl), —N(C₁-C₈alkyl)(C₃-C₈cycloalkyl), heteroalkyl or substituted heteroalkyl wherein the substituent on the heteroalkyl is selected from oxo, amino, C₁-C₈ alkoxyC₁-C₈ alkyl, C₁-C₈ alkylamino or C₁-C₈ dialkylamino; R₂ and R₃ are each independently selected from hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₈ alkyl, aryl, heteroalkyl, substituted heteroalkyl (wherein the substituent on the heteroalkyl is one or more substituents independently selected from C₁-C₈ alkoxycarbonyl, C₁-C₈ alkyl, or C₁-C₄ alkylcarbonyl), heteroalkylC₁-C₈ alkyl, indanyl, acetamidinoC₁-C₈ alkyl, aminoC₁-C₈ alkyl, C₁-C₈ alkylaminoC₁-C₈ alkyl, C₁-C₈ dialkylaminoC₁-C₈ alkyl, unsubstituted or substituted heteroarylC₁-C₈ alkyl or unsubstituted or substituted arC₁-C₈ alkyl, wherein the substituent on the aralkyl or heteroarylalkyl group is one or more substituents independently selected from halogen, nitro, amino, C₁-C₈ alkyl, C₁-C₈ alkoxy, hydroxy, cyano, C₁-C₄ alkylcarbonyl, C₁-C₈ alkoxycarbonyl, hydroxyC₁-C₈ alkyl or aminosulfonyl; R₂ and R₃, together with the nitrogen to which they are attached, alternatively form an unsubstituted or substituted heteroalkyl group selected from piperidinyl, piperazinyl, morpholinyl or pyrrolidinyl, wherein the substituent is one or more substituents independently selected from C₁-C₈ alkyl C₁-C₈ alkoxycarbonyl or C₁-C₄ alkylcarbonyl; R₄ is selected from unsubstituted or substituted aryl, arC₁-C₈ alkyl, C₃-C₈ cycloalkyl, or heteroaryl, where the substituents on the aryl, arC₁-C₈ alkyl, cycloalkyl or heteroaryl group are independently selected from one or more of halogen, nitro, amino, cyano, hydroxyalkyl, C₁-C₈ alkyl, C₁-C₈ alkoxy, hydroxy, C₁-C₄ alkylcarbonyl, C₁-C₈ alkoxycarbonyl, fluorinated C₁-C₄ alkyl, fluorinated C₁-C₄ alkoxy, C₁-C₄ alkylsulfonyl; m is 1 and n is 2; comprising reacting a compound of the formula AAG6: H-A₁-A₂-NR₂R₃, with a compound of the formula AAG4:

in the presence of a phosgene equivalent to form the compound of formula (II). 